Doxorubicin hydrochloride (HCl) is an antineoplastic agent which is highly effective and has a broad spectrum of activity against many forms of cancer. It is the most widely used antineoplastic in many countries including the USA and Western Europe. Doxorubicin HCl is often included in multi-drug regimens and has become the mainstay of chemotherapy. This drug is marketed in North America by Adria Laboratories, Division of Erbamont Inc., under the trademark "Adriamycin."
A serious side effect which may result from cumulative doses of doxorubicin HCI exceeding 550 mg/m.sup.2 is irreversible myocardial toxicity with delayed congestive heart failure often unresponsive to cardiac support therapy. This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy.
Clinical studies have shown that the compound (S)-(+)-bis-4,4'-(1-methyl-1,2-ethanediyl)2,6-piperazinedione (ADR-529, formerly referred to as ICRF-187), is a cardioprotective agent which can reduce or prevent the myocardial toxicity resulting from administration of doxorubicin HCl. (See Green et al, PROC. ASCO, 1987 6:28). Other highly desirable properties of ADR-529 are activity as a divalent cation chelating agent, sensitizer to ionizing radiation, anti-metastic agent and synergistic agent with anthracyclines in terms of anti-tumor effect.
ADR-529 is prepared as a lyophilized white powder according to conventional lyophilization techniques well known in the art. Briefly, this process involves the steps of preparing an aqueous solution of ADR-529, filling this solution into glass vials and thereafter sublimating the water under vacuum in a lyophilizer. The lyophilizate is reconstituted with a suitable pharmaceutically acceptable diluent, e.g., 0.9% sodium chloride solution to give a solution, which may thereafter be intravenously administered to a patient.
The present recommended clinical dose of ADR-529 is 1 g/m.sup.2 of body surface. Currently, depending on the body weight of the patient, the clinician must reconstitute 4 to 8 vials containing 250 mg of lyophilized ADR-529 per vial.
The contents of the reconstituted vials are pooled into an IV bag and the pooled contents are administered to a patient by infusion over 15 minutes. It can be appreciated that it would be highly desireable to minimize the number of vials to be reconstituted and to reduce the possibility of cross contamination of the final solution due to pooling of the reconstituted portions.
The largest standard vial size which is conventionally used in the lyophilizer is 100 cc. Generally, the solution to be lyophilized is added to the via- so as to occupy about one-half of the volume of the vial. If the vial is filled any fuller, it is difficult to establish steady state vapor pressure and as a result, the lyophilization cycle is slowed significantly. Also, there will not be enough room for the solution to expand in the vial upon freezing and, when the frozen solution expands, the vial may break. The breakage is high for large volume vials because they are weak.
The solubility of ADR-529 in water is 10 mg/mL at 25.degree. C. Accordingly, one (1) gram of ADR-529 will not dissolve in 50 mL of water which is about the maximum amount of solution which should be added to a 100 cc vial for the subsequent lyophilization process.
Of course, a vial with a nominal fill volume of 200-220 mL could be used. There are however, significant disadvantages to using a larger vial size. Most vial filling equipment is designed to fill conventional 100 cc vials. Development of alternative equipment would be both time consuming and expensive. Further, the lyophilization cycle will take longer because larger volumes of liquid must be removed plus fewer vials can be processed during the lyophilization cycle since the larger vials occupy more space in the lyophilizer.
It can be appreciated that it would be highly desirable to be able to increase the solubility of ADR-529 in water so as to get one gram of ADR-529 dissolved in 50 mL of water. This would allow for subsequent lyophilization in 100 cc vials using conventional filling equipment and lyophilization techniques.
Another disadvantage of conventional lyophilized ADR-529 is that the lyophilized material has a tendency to convert to the crystalline form upon storage at ambient temperature. The presence of even a small amount of crystals in the lyophilizate greatly increases the dissolution rate (i.e., reconstitution time) of the lyophilizate from about 30 sec. to about 15 min. The conversion of ADR-529 from the amorphous to the crystalline form appears to be related to the moisture in the lyophilizate. The presence of greater then 2% moisture in the lyophilizate will result in formation of crystals. To prevent crystal formation, conventional lyophilized vials of ADR-529 should be stored under refrigeration.
It is therefore an object of the invention to prepare a lyophilizate of ADR-529 which is stable at room temperature for about 2 years and which has a dissolution time of about 1 sec. to about 5 sec. when reconstituted with a pharmaceutically acceptable diluent so as to produce an isotonic solution suitable for intravenous injection into a patient.
It is yet another object of the invention to prepare a lyophilizate of ADR-529 using conventional 100 cc vials as well as conventional filling and lyophilization equipment.
Yet, a further embodiment of the invention is directed to an injectable isotonic solution having a pH of about 3.0 to about 6.0, which contains about 10 mg/mL of the active drug substance (ADR-529).